[Comparison of Preparation Efficiency and Therapeutic Safety between Brand-Name and Generic Products of Pemetrexed].

At Oita University Hospital, we switched our usage of pemetrexed(PEM)from brand-name to generic drugs. We conducted a comparative study of the preparation efficiency and therapeutic safety with the brand-name product and examined the economic effect thereof. The incidence of adverse drug reactions was investigated retrospectively using electronic medical records for patients who received PEM brand-name and generic drugs at our hospital between April 2021 and December 2022. The preparation time per mg was significantly shorter in the generic group at 0.17(0.08-0.38)seconds compared to 0.34(0.15-0.94)seconds for the brand-name group(p<0.01). Regarding the safety comparison, none of the 13 eligible patients developed new hematologic or non-hematologic toxicities of Grade 2 or higher after switching to the generic product. The switch to generics had an economic impact of 7,369,278 yen during the study period. The results suggest that switching from brand-name to generic products is reasonable from the perspectives of therapeutic safety and economic benefits, as well as the expected improvement in preparation efficiency.

Cathepsin G-induced malignant progression of MCF-7 cells involves suppression of PAF signaling through induced expression of PAFAH1B2.

Breast cancer is primarily classified into ductal and lobular types, as well as into noninvasive and invasive cancer. Invasive cancer involves lymphatic and hematogenous metastasis. In breast cancer patients with distant metastases, a neutrophil-derived serine protease; cathepsin G (Cat G), is highly expressed in breast cancer cells. Cat G induces cell migration and multicellular aggregation of MCF-7 human breast cancer cells; however, the mechanism is not clear. Recently, platelet-activating factor (PAF)-acetylhydrolase (PAF-AH), the enzyme responsible for PAF degradation, was reported to be overexpressed in some tumor types, including pancreatic and breast cancers. In this study, we investigated whether PAF-AH is involved in Cat G-induced aggregation and migration of MCF-7 cells. We first showed that Cat G increased PAF-AH activity and elevated PAFAH1B2 expression in MCF-7 cells. The elevated expression of PAFAH1B2 was also observed in human breast cancer tissue specimens by immunohistochemical analysis. Furthermore, knockdown of PAFAH1B2 in MCF-7 cells suppressed the cell migration and aggregation induced by low concentrations, but not high concentrations, of Cat G. Carbamoyl PAF (cPAF), a nonhydrolyzable PAF analog, completely suppressed Cat G-induced migration of MCF-7 cells. In addition, PAF receptor (PAFR) inhibition induced cell migration of MCF-7 cells even in the absence of Cat G, suggesting that Cat G suppresses the activation of PAFR through enhanced PAF degradation due to elevated expression of PAFAH1B2 and thereby induces malignant phenotypes in MCF-7 cells. Our findings may lead to a novel therapeutic modality for treating breast cancer by modulating the activity of Cat G/PAF signaling.

Development of a Sensitive and High-Throughput Assay for Simultaneous Quantification of 5 Tyrosine Kinase Inhibitors and 2 Active Metabolites in Human Plasma Using Ultra-high Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry.

BACKGROUND: Breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitors (TKIs) demonstrate improved therapeutic efficacy in chronic myeloid leukemia (CML). However, drug-drug interactions, nonadherence, and host-related factors may influence plasma concentrations. Therefore, therapeutic drug monitoring may be necessary for patients presenting inadequate treatment responses or adverse events. Herein, the authors aimed to develop a more sensitive and high-throughput method than those previously reported to simultaneously quantify 5 TKIs (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib) and 2 active metabolites (N-desmethyl imatinib and N-desmethyl ponatinib) using ultra-performance liquid chromatography coupled with tandem mass spectrometry. METHODS: Plasma samples were prepared according to a solid-phase extraction protocol using an Oasis MCX µElution plate. The assay fulfilled the requirements of the US Food and Drug Administration for assay validation, with a lower limit of quantification of 0.2 ng/mL for dasatinib, 0.3 ng/mL for N-desmethyl ponatinib, 0.5 ng/mL for N-desmethyl imatinib, bosutinib, and ponatinib, and 2.5 ng/mL for imatinib and nilotinib. RESULTS: Within-batch and batch-to-batch precision at the lower limit of quantification and quality control levels were within 14.3% and 10.9%, respectively. Within-batch and batch-to-batch accuracies ranged from 15.5% to 13.0% and 5.70% to 7.03%, respectively. A positive electrospray ionization mode was used with a run time of 6.0 minutes. The assay applicability was verified by the successful measurement of 78 clinical samples from patients undergoing CML therapy. CONCLUSIONS: The method allows assessment of trough concentrations of TKIs and active metabolites in patients with CML, and hence can be used to assess blood samples in routine clinical settings.

Exacerbation of cancer pain after administering immune checkpoint inhibitor in a patient taking opioids: A case report.

WHAT IS KNOWN AND OBJECTIVE: Clinical cases of attenuation of opioid analgesic effect by administration of immune checkpoint inhibitors has not been reported. We present a case of head and neck cancer under pain management with opioids, in which cancer pain was exacerbated after administration of nivolumab. CASE SUMMARY: A male patient with head and neck cancer was hospitalized for the second-line treatment of nivolumab. He had complained of head and neck pain after admission, but the pain was especially worse after nivolumab administration. The dose of opioids was eventually increased by approximately 320% (morphine equivalent dose) compared to before administering nivolumab. WHAT IS NEW AND CONCLUSION: When administering immune checkpoint inhibitors such as nivolumab in clinical practice, the possibility of attenuation of opioid analgesic effect should be considered.

Successful determination of imatinib re-administration dosage by therapeutic drug monitoring in a case of chronic myeloid leukemia initiating dialysis for acute renal dysfunction.

Fixed dose regimen is currently the standard administration method for TKI. However, this case report indicated that TDM may by a useful approach to individualized dosing of TKI for the treatment of CML when initiating dialysis.

[Comparison of Treatment Safety Between Brand-Name Product and Biosimilar of Trastuzumab].

At the Oita University Hospital, we switched from using the original biological product of trastuzumab(original product) to a biosimilar product, and verified the appropriateness of the switch by investigating the occurrence of adverse events. We compared the safety of the original and biosimilar products from January 2019 to September 2020. Of 14 cases studied, there were 6 in the original product group, 6 in the switched group, and 2 in the biosimilar group. In 3 patients in the switched group, infusion reaction was observed during administration of the original product, and was appropriately managed at that time. After switching to the biosimilar product, it was possible to administer the drug safely even when the infusion time was shortened. The results of this study showed that no adverse events were observed after switching from the original to the biosimilar product. This finding suggests that switching products is appropriate, not only from an economic point of view but also from the perspective of treatment safety.

Successful determination of nilotinib dosage by therapeutic drug monitoring in a patient with chronic myeloid leukemia developing hepatic dysfunction: A case report.

Fixed dosage regimen is currently the standard therapy with tyrosine kinase inhibitors (TKI). This case report demonstrates successful determination of nilotinib dosage by therapeutic drug monitoring (TDM) in a patient with chronic myeloid leukemia (CML). TDM may provide useful marker for individualized dosing of TKI for the treatment of CML.

A quantitative method for the determination of bosutinib in human plasma using high-performance liquid chromatography and ultraviolet detection.

BACKGROUND: We propose a simple, sensitive, and fast high-performance liquid chromatography ultraviolet detection (HPLC-UV) method for the quantitative determination of bosutinib in human plasma. METHODS: Plasma samples were processed using an Oasis hydrophilic-lipophilic balance extraction cartridge (1 mL, 30 mg). Bosutinib and the internal standard imatinib were separated using a mobile phase of 0.5% Na2 PO4 H2 O (pH 3.5)-acetonitrile-methanol (55:25:20, v/v/v) on a CAPCELL PAK C18 MG II reversed-phase column 250 nm×4.6 nm i.d., at a flow rate of 1.0 mL/min, with ultraviolet detection at 250 nm. RESULTS: The calibration curve exhibited linearity over the bosutinib concentration range of 25-1500 ng/mL at 250 nm, with coefficient of variation for intraday precision of 2.42%, 6.04%, and 1.11% for 100, 250, and 1500 ng/mL, respectively, of bosutinib. The lower limit of detection was 20 ng/mL. The extraction recovery rates for bosutinib ranged from 84.36% to 85.82%. The intra- and interday precision was below 8.7%, and the accuracy ranged from -5.95% to 5.85% over the linear range. No notable matrix effects or astaticism were observed. CONCLUSION: The proposed HPLC-UV method was successfully applied as an assay to detect bosutinib in human plasma.